DESCRIPTION (Adapted from applicant's abstract and specific aims): The goal of this project is to determine the role of granule-associated neutral serine proteinases of polymorphonuclear leukocytes in lung health and disease, focusing, in particular, on the involvement proteinase 3 (PR-3) and leukocyte elastase (LE) in the pathogenesis of emphysema. The proposed studies are based on the following hypotheses: 1) PR-3 and LE are regulated by novel transcription factors, including one that binds to a CG-rich element, that account for their exquisite tissue-and developmental-specific expression; 2) Dipeptidyl peptidase-I (DPP-I), a cysteine proteinase, coordinates the activation of PR-3 and LE, and offers a control point for their expression; and 3) PR-3 and LE are critically important in the pathogenesis of emphysema not only due to their ability to degrade extracellular matrix, but also for because of their attack on intracellular components leading to cell death. The specific aims are to 1) determine the regulatory elements and factors that dictate PR-3 and LE gene expression; 2) characterize the dipeptidase responsible for activating PR-3 and LE; and 3) determine the role of PR-3 and LE in the development and progression of emphysema.